Mechanism of Medroxyprogesterone Acetate Against Endometrial Cancer Based on Network Toxicology and Molecular Docking

Corresponding author: Zhai Tingting, Ztt1995wym@163.com

DOI: 10.12201/bmr.202606.00065

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  Abstract: AbstractObjective: To systematically predict the potential targets of medroxyprogesterone acetate (MPA) against endometrial cancer (EC) and explore its multi-target, multi-pathway molecular mechanism based on network toxicology and molecular docking.Methods: MPA-related targets were obtained from the CTD, STITCH, and SwissTargetPrediction databases; EC-related disease targets were retrieved from GeneCards, OMIM, and TTD databases. Cytoscape software was used to construct an MPA-target-EC network and a protein–protein interaction (PPI) network, and core targets were screened via topological analysis. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the core targets. Finally, molecular docking verification was conducted for the top five core targets.Results: A total of 410 MPA-related targets, 2312 EC-related genes, and 165 overlapping targets were identified. The core targets mainly included TP53, FN1, TNF, ESR1, and FOXO1. GO enrichment analysis showed that the core targets were mainly enriched in biological processes such as reactive oxygen species metabolic process, gland development, regulation of apoptotic signaling pathway, response to hypoxia, regulation of smooth muscle cell proliferation, and estrogen response element binding. KEGG pathway enrichment was observed in the PI3K-Akt, FoxO, p53, HIF-1, HPV, and steroid hormone biosynthesis signaling pathways. Molecular docking verification demonstrated that MPA exhibited strong binding affinity with core targets including TP53, FN1, and ESR1 (binding free energy ΔG < ?8.0 kcal/mol).Conclusion: Medroxyprogesterone acetate (MPA) may exert anti-endometrial cancer (EC) effects by regulating multiple targets such as TP53, FN1, TNF, ESR1, and FOXO1, interfering with multiple signaling pathways including PI3K-Akt, FoxO, p53, HIF-1, HPV, and steroid hormone biosynthesis, and affecting tumor suppression, cell proliferation, apoptosis, hypoxic stress, inflammatory response, hormone regulation, and hormone response in tumor microenvironment remodeling. However, its high predicted toxicity risk suggests that caution is required in clinical application. The results of this study provide a new hypothesis for the multi-target mechanism of MPA in the treatment of EC.

  Key words: medroxyprogesterone acetate; endometrial cancer; network toxicology; molecular docking; mechanism of action

  Submit time: 21 June 2026

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
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